Analysis of Manganese Tracer Kinetics and Target Tissue Dosimetry in Monkeys and Humans with Multi-Route Physiologically Based Pharmacokinetic Models

Abstract

Manganese (Mn) is an essential nutrient with the capacity for toxicity from excessive exposure. Accumulation of Mn in the striatum, globus pallidus, and other midbrain regions is associated with neurotoxicity following high-dose Mn inhalation. Physiologically based pharmacokinetic (PBPK) models for ingested and inhaled Mn in rats and nonhuman primates were previously developed. The models contained saturable Mn tissue-binding capacities, preferential fluxes of Mn in specific tissues, and homeostatic control processes such as inducible biliary excretion of Mn. In this study, a nonhuman primate model was scaled to humans and was further extended to include iv, ip, and sc exposure routes so that past studies regarding radiolabeled carrier-free (54)MnCl(2) tracer kinetics could be evaluated. Simulation results accurately recapitulated the biphasic elimination behavior for all exposure routes. The PBPK models also provided consistent cross-species descriptions of Mn tracer kinetics across multiple exposure routes. These results indicate that PBPK models can accurately simulate the overall kinetic behavior of Mn and predict conditions where exposures will increase free Mn in various tissues throughout the body. Simulations with the human model indicate that globus pallidus Mn concentrations are unaffected by air concentrations < 10 μg/m(3) Mn. The use of this human Mn PBPK model can become a key component of future human health risk assessment of Mn, allowing the consideration of various exposure routes, natural tissue background levels, and homeostatic controls to explore exposure conditions that lead to increased target tissue levels resulting from Mn overexposure.

Relationship between concentrations of heavy metals in children’s scalp hair and the environment. A case study from Kifissos River in Attica, Greece.

“…Inhalation is the most important route of exposure for children, because very small inhaled particles that deposit on lung epithelium bypass uptake control in the gastrointestinal tract and liver entering directly in the systemic circulation (Schroeter et al, 2011). Chronic exposure to severe urban air pollution causes a significant imbalance in genes essential for cell proliferation, apoptosis, oxidative stress, inflammation, innate and adaptive immune responses and early Alzheimer's diseaserelated pathological processes leading to neurofibrillary tangle formation start early in childhood or in early young adulthood (Calderón-Garciduenasc et al, 2012).…”

Modeling Manganese Kinetics for Human Health Risk Assessment

“…This tissue description served as the basis for a series of Mn models subsequently covering different species and life stages. [36][37][38][39][40] These models, referred as ''second generation'' of Mn PMPK models in the review by Taylor and colleagues, 41 were developed in a stepwise fashion with increasing model complexity added sequentially to the basic description ( Figure 13.2). The basic model structure was developed and evaluated in the rat first because the available PK data are most extensive in this species.…”

“…36,37 The monkey model was viewed as a critical step in the evolution of appropriate human models. Most structural features of the rat model were retained in order to maintain consistent descriptions of the controlling processes in Mn distribution, and physiological processes were scaled as appropriate between species.…”

“…However, direct scaling of Mn kinetic parameters from the rat did not provide a good description of Mn tissue kinetics in the monkey. 37 Some of these parameters required further adjustment after generic allometric scaling approaches were attempted. 37 However, it bears emphasis that the description of underlying mechanisms governing Mn uptake and elimination in the model-inducible biliary excretion, tissue binding processes, and asymmetric diffusion fluxes-were preserved for all species, providing a consistent model structure.…”

“…37 Some of these parameters required further adjustment after generic allometric scaling approaches were attempted. 37 However, it bears emphasis that the description of underlying mechanisms governing Mn uptake and elimination in the model-inducible biliary excretion, tissue binding processes, and asymmetric diffusion fluxes-were preserved for all species, providing a consistent model structure. Further experiments would be helpful to determine the specific transporters involved in uptake and efflux from tissues and the nature of the binding sites.…”